New, Safe Technique To Expand CD4+ Cells Discovered

VANCOUVER, BC--Expansion of CD4+ cells could help reconstitutethe immune system in patients with AIDS. However, this approachhas been unfeasible because stimulation of a patient's CD4+ cellsto replicate also leads to HIV replication and greater cell death.

Now, Bruce L. Levine, PhD, and colleagues at the Naval MedicalResearch Institute have identified a CD28-mediated effect thatmay permit the generation of large numbers of CD4+ T cells withoutincreased HIV replication.

Dr. Levine reported at the 11th International Conference on AIDSthat ex vivo co-stimulation of the CD28 receptor on CD4+ T cellscan lead to polyclonal expansion of CD4+ cells from HIV-infecteddonors, resulting in a large stock of new uninfected CD4+ T cells.

Activated cells secreted predominantly cytokines associated withT helper type I function. HIV-1 specific expression and proviralDNA load declined during culture, Dr. Levine said.

"Our results demonstrate that proliferation of polyclonalHIV-1 uninfected CD4+ T cells from HIV-infected donors is possible,"he noted. This effect occurred without the use of antiretroviraldrugs.

CD28 stimulation also made unin-fected CD4+ T cells "highlyresistant to HIV-1 infection," Dr. Levine said. This effectdid not require the presence of CD8+ cells, and it was dependenton how the CD28 receptor was activated.

Exposure to immobilized anti-CD28 antibodies made CD4+ T cellsresistant to HIV, but stimulation with soluble anti-CD28 madethem more susceptible to infection.

To Dr. Levine, this suggests that ex vivo proliferation of CD4+T cells may permit immune reconstitution as well as vaccine therapiesthat involve transfusing autologous but uninfected CD4+ T cellsback into patients with HIV.

The group is currently running a phase I trial at the Naval Hospitalusing three increasing doses of CD4+ cells; three HIV-infectedpatients have been treated on the protocol so far.

There have also been preliminary discussions about using the techniquein immunosuppressed cancer patients, Dr. Levine said, and theNaval Institute team is looking for cancer investigators who wouldbe interested in collaborating on this research.